Dry powder inhaler

ABSTRACT

A dry powder inhaler includes a chamber holding an actuator to which a powdered medicament is adhered. Air is drawn into the chamber through an inlet flow channel and exits through an outlet flow channel. The actuator oscillates in response to the air flow, dislodging powdered medicament to be entrained in the air flow and delivered to the patient. A retaining member prevents the actuator from exiting the chamber. Thus, the medicament may be delivered to the patient without the use of carrier particles.

This application claims priority to U.S. Provisional Application No.61/420,639 filed Dec. 7, 2010 and titled “Dry Powder Inhaler” and toU.S. Provisional Application No. 61/442,872 filed Feb. 15, 2011 andtitled “Dry Powder Inhaler”, the entire disclosures of which are herebyincorporated by reference herein.

BACKGROUND OF THE INVENTION

The benefits of inhaled therapy for treatment of lung diseases such asasthma, chronic obstructive pulmonary disease (COPD), and cysticfibrosis have been recognized for many years. Direct administration ofdrug to the airways minimizes systemic side effects, provides maximumpulmonary specificity, and imparts a rapid onset of action.

Dry powder inhalers (DPIs) are becoming a leading device for delivery oftherapeutics to the airways of patients. Currently, all marketed drypowder inhalation products are comprised of micronized drug (eitheragglomerated or blended) delivered from “passive” dry powder inhalers,DPIs. These inhalers are passive in the sense that they rely on thepatient's inspiratory effort to disperse the powder into a respirableaerosol.

Despite their popularity and the pharmaceutical advantages over otherinhaler types, passive dry powder inhalers typically have relativelypoor performance with regard to consistency. In particular, DPIs emitdifferent doses depending on how the patient uses the device, forexample, the inhalation effort of the patient.

Also, the efficiency of DPIs can be quite poor. In one study comparingthe performance of the two most widely prescribed DPIs, only between 6%and 21% of the dose emitted from the device was considered respirable.Improved performance for DPI devices is desperately needed from bothclinical and product development standpoints. One promising approach toimproving DPI performance is to modify the formulation rather than thedevice itself.

Conventional formulations for dry powder inhalation aerosols typicallycontain micronized drug of particle sizes small enough to enter theairways and be deposited in the lung. To make these highly cohesive andvery fine particles dispersible, so called “carrier” particles are mixedwith the drug particles. These coarse, and pharmaceutically inactive (orinert), carrier particles are found in nearly all dry powder inhalerproducts currently marketed. The carrier particles serve to increase thefluidization of the drug because the drug particles are normally toosmall to be influenced significantly by the airflow through the inhaler.The carrier particles thus improve the dose uniformity by acting as adiluent or bulking agent in the formulation.

Although these carrier particles, which are generally about 50-100microns in size, improve the performance of dry powder aerosols, theperformance of dry powder aerosols remains relatively poor. Forinstance, only approximately 30% of the drug in a typical dry powderaerosol formulation will be delivered to the target site, and often muchless. Significant amounts of drug are not released from theseconventional carrier particles and, due to the relatively large size ofthe carrier in relation to the drug, the drug is deposited in the throatand mouth of the patient where it may exert unwanted side effects.

A dry powder formulation is typically a binary mixture, consisting ofmicronized drug particles (aerodynamic diameter typically between 1 and5 μm) and larger inert carrier particles (typically lactose monohydratewith 63-90 μm diameters). Drug particles experience cohesive forces withother drug particles and adhesive forces with carrier particles(predominately via van der Waals forces), and it is theseinterparticulate forces that must be overcome in order to effectivelydisperse the powder and increase lung deposition efficiency. The energyused to overcome the interparticulate forces is provided by the inspiredbreath of the patient as they use the inhaler. The aerodynamic forcesentrain and de-aggregate the powder, though variations in the inhalationeffort of the patient (e.g. such as those arising from fibrosis orobstruction of the airways) significantly affect the dispersion anddeposition of the drug, producing the flow-rate dependency of theinhaler. Obviously, there is a need for improved dry powder formulationsemploying novel carrier particles to maximize the safety and efficacyprofiles of current DPI inhalers.

The active pharmaceutical ingredient (API), also called a medicament,typically constitutes less than 5% of the formulation (% w/w), withlactose comprising the vast majority of the dose. The purpose of thecarrier lactose is to prevent aggregation of the drug particles due tocohesive forces, primarily van der Waals forces arising from theinstantaneous dipole moments between neighboring drug particles. Due tothe small size of the drug particles these resulting cohesive forces arequite strong and not readily broken apart by the aerodynamic forceprovided by inhalation, producing aggregates that possess poor flowproperties and end up depositing in the back of the throat. By employinga binary mixture, the drug adheres to the carriers particles instead andthe larger size of the carrier particles allows them to be more easilyentrained in the air stream produced when the patient inhales, carryingthe API toward a mesh where the carrier particle collides; the forcefrom the collision is often sufficient to detach the drug particles fromthe carrier, dispersing them in the airstream and allowing theirdeposition within the lung. Collisions with the inner walls of theinhaler may also be significant. However, a large fraction of APIremains attached to carriers that do not collide effectively with themesh, but instead are deflected, producing insufficient force todisperse the drug particles from its surface. API that does notdissociate from these carriers, along with drug adhered to carrierparticles that slip through without any contact with the mesh, aredeposited in the back of the throat via inertial impaction, oftencausing significant side effects in the throat.

Over the past twenty years considerable research into the optimalproperties of DPI formulations has been conducted. DPI formulations haverequired larger inert carrier particles to be blended with the smallmicronized (<5 microns) drug particles to improve re-dispersion of thecohesive drug particles and reduce dosing variability. Without carrierparticles, micronized drug remains aggregated and almost all is simplyinhaled as far as the throat, where it is swallowed and never reachesthe intended target. There have been many studies investigating thesecarrier particles yet modifications to their physiochemical properties(size, shape, crystallinity, surface fines, roughness, etc) have failedto yield meaningful improvements in performance of DPIs. Moreover, thesecarrier particles (lactose in the US), are also responsible for batch tobatch variability in DPI performance. One of the most commonly studiedproperties of carrier particles is carrier particle diameter. Over thecourse of 20 years, the general rule of thumb has been established thatincreasing carrier particle size leads to decreased DPI performance.FIG. 1 shows several examples from previous literature that indicatedthat increasing carrier particle size in DPI formulations leads todecreased performance.

Some conventional DPIs permit, and sometimes even intend, carrierparticles to exit the inhaler. As a result, the carrier particles mustbe inert, and in the United States, the FDA restricts the carrierparticle material to lactose. There is thus a need for advancedformulation technologies including alternative carrier particlematerials that may be more judiciously chosen based on hygroscopicproperties of the carrier (e.g., a desiccant material) and the surfaceinteractions (e.g., acid or base character of the drug and carrier)between the carrier and the drug. As such, it may be desirable toprovide a DPI that is completely void of carrier particles to allow forcircumventing the FDA restriction of lactose as the carrier material.

Nasal delivery is used for treatment of a variety of illnesses such asallergic rhinitis, as well as for delivery of drugs for systemic or CNSaction.

Both powder and liquid nasal delivery systems are currently on themarket. The liquid delivery technologies have utilized spray pumpderived technology or pressurized metered dose inhalers (pMDIs) forrapid jetting of the formulation into the nasal cavity. In general,nasal formulations are solution or suspension based requiring solventsor stabilizers. These are typically administered as sprays. Meteredsprays and pump sprays have several disadvantages including:

-   -   Need for priming in order to secure “dose uniformity”    -   Complicated and expensive designs, involving many device parts        in different materials.    -   The devices are difficult to manufacture    -   Formulations are less stable    -   Control over deposition site in nasal cavity is poor    -   Deposition of formulation is often concentrated to certain        tissues and causes irritation on these areas while not treating        other locations within the nasal cavity    -   Positioning of the device during use is critical and heavily        dependent on patient use, therefore variability in dosing to        target tissues is high

DPI device technologies have been applied to nasal deliverypredominantly for locally acting drugs. These formulations have notableadvantages such as stability and dose delivery. These can beparticularly advantageous for biological drugs and drugs requiringsystemic plasma concentrations. Included in these systems are modifieddry powder inhalers (developed for orally inhaled aerosol delivery) witha “nostril piece” instead of a “mouth piece”. Such devices are activatedby nasal inhalation. These devices have also applied known concepts fromDPI technology: reservoir dry powder with dose metering mechanisms—orcapsule based devices needing piercing mechanisms and special loadingprocedures before use and after use. These device concepts inherit thesame problems experienced when using DPIs for pulmonary delivery:complicated formulation, and high airflow resistance making it difficultto achieve sufficient nasal dose delivery.

To solve these device resistance problems, insufflators that “blow” thepowder formulation of the drug into the nostril have been designed. Inmechanical terms these devices are “bulky” and with limited portability,and impossible to operate with discretion. In addition, they suffer fromthe same in-use variability and regional deposition drawbacks of spraysystems.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed generally to dry powder inhalationaerosols and methods of delivering drug and/or therapeutic agents to apatient. More particularly, the present invention is designed todirectly apply active agents to patients utilizing a novel actuatingsphere design and an accompanying inhaler to take advantage of theseunique properties. In some embodiments, the present invention also takesadvantage of the high performance at low flow rates of a powderdispersion system so that powders can be successfully delivered todifferent regions of the nasal cavity.

According to one aspect, a dry powder inhaler includes an inlet channelthrough which air enters the inhaler, and a chamber that receives airfrom the inlet channel, the chamber being of a size and shape to containan actuator to which a powdered medicament is adhered. The dry powderfurther includes a retaining member disposed at an end of the chamberopposite the inlet channel, the retaining member having one or moreopenings sized to permit air and the powdered medicament to pass throughthe retaining member, and to prevent the actuator from passing throughthe retaining member, and an outlet channel through which air and thepowdered medicament leave the inhaler to be delivered to a patient. Thegeometry of the inhaler is such that a flow profile is generated withinthe chamber that causes the actuator to oscillate, thus detaching thepowdered medicament from the surface of the actuator to be entrained bythe air and delivered to the patient through the outlet channel. In someembodiments, the cross sectional area of the flow path through theinhaler undergoes a step increase at the entrance to the chamber. At theentrance to the chamber, the diameter of the chamber may be at least 1.5times the diameter of the inlet channel. The inlet channel may comprisea tapered tube. The outlet channel may comprise a tube whose crosssection changes along the length of the tube. In some embodiments, theoutlet channel is comprised in a mouthpiece adapted to be placed withinthe mouth of the patient. In some embodiments, the outlet channel iscomprised in a nasal adapter adapted to conform to the nostrils of thepatient.

The dry powder inhaler may further comprise one or more bypass channelsthat receive supplemental air from outside the inhaler and deliver thesupplemental air to the patient without the supplemental air havingpassed through the chamber. In some embodiments, the inlet channel is afirst inlet channel and the chamber is a first chamber, the dry powderinhaler further comprises a second inlet channel and a second chamber.In some embodiments, air and powdered medicament leaving the first andsecond chambers are delivered to the outlet channel. In someembodiments, the outlet channel is a first outlet channel, the drypowder inhaler further comprises a second outlet channel, and air andpowdered medicament leaving the first chamber are delivered to the firstoutlet channel, and air and powdered medicament leaving the secondchamber are delivered to the second outlet channel. The first and secondchambers may be of the same dimensions. The dry powder inhaler may beseparable to permit insertion of a capsule into the chamber, the capsulecontaining the actuator. The dry powder inhaler may further includefeatures for puncturing seals at ends of the capsule. Airflow throughthe inhaler may be driven by inspiratory effort of the patient.

In some embodiments, the dry powder inhaler is combined with theactuator. The actuator may be made of expanded polystyrene. The actuatormay have a density between 0.001 and 0.50 g/cm³. The actuator may have adiameter of at least 1000 microns. The actuator may have a diameterbetween 1000 and 6000 microns. In some embodiments, a combination ofmedicaments is adhered to the actuator. In some embodiments, the drypowder inhaler includes a plurality of chambers disposed on a rotaryelement for selectively aligning any of the chambers with the outletchannel.

According to another aspect, a method comprises obtaining a dry powerinhaler that includes an inlet channel, a chamber, and an outletchannel, the chamber holding an actuator, wherein one or more powderedmedicaments are adhered to an outside surface of the actuator; andinhaling through the outlet channel, causing air to flow into the inletchannel, through the chamber, and through the outlet chamber, theflowing air also causing the actuator to oscillate to dislodge powderedmedicament from the surface of the actuator to be entrained in theflowing air and carried through the outlet channel. In some embodiments,the method further includes separating portions of the inhalercomprising the chamber and the outlet channel, loading the actuator intothe chamber, and re-engaging the two portions of the inhaler. Acombination of powdered medicaments may be adhered to the actuator. Insome embodiments, the dry powder inhaler includes at least two chambersholding at least two actuators having medicament adhered to theactuators, and wherein the flowing air causes each actuator to oscillateto dislodge powdered medicament to be inhaled. The same powderedmedicament may be adhered to at least two actuators. In someembodiments, at least two actuators have different powdered medicamentsadhered to the actuators.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows several examples from previous literature indicating therelationship of carrier particle size in DPI formulations to DPIperformance.

FIGS. 2A-2C illustrate certain principles utilized by embodiments of theinvention.

FIG. 3 illustrates relative adhesion and detachment forces as a functionof carrier size.

FIG. 4A shows an oblique view of a dry powder inhaler (DPI), accordingto an embodiment of the invention.

FIG. 4B shows a side view of the DPI of FIG. 4A.

FIG. 4C shows a section view of the DPI of FIG. 4A.

FIG. 4D illustrates the DPI of FIG. 4A in operation.

FIG. 5A shows an oblique view of a DPI according to another embodiment.

FIG. 5B is a cross section view of the DPI of FIG. 5A.

FIG. 6 illustrates a cross section of an alternative chamber portion,according to embodiments of the invention.

FIG. 7 illustrates a cross section view of a DPI according to anotherembodiment.

FIG. 8A illustrates an oblique view of a chamber portion in accordancewith another embodiment.

FIG. 8B shows a cross section view of the chamber portion of FIG. 8A.

FIGS. 8C and 8D illustrate two alternative arrangements for connectingthe multiple chambers to one or more outlet flow channels, according toembodiments of the invention.

FIG. 9A illustrates an oblique view of a chamber portion in accordancewith another embodiment.

FIG. 9B shows a cross section view of the chamber portion of FIG. 9A.

FIG. 9C shows a cross section view of a DPI using the chamber portion ofFIG. 9A, according to an embodiment of the invention.

FIG. 10 illustrates a cartridge, in accordance with an embodiment.

FIG. 11 illustrates steps in one method of producing the cartridge ofFIG. 10, in accordance with an embodiment.

FIG. 12 illustrates additional steps in a method of producing thecartridge of FIG. 10, in accordance with an embodiment.

FIG. 13 illustrates a multi-dose inhaler according to an embodiment ofthe invention.

FIG. 14 illustrates the multi-dose inhaler of FIG. 13, after loading.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

In the description which follows like parts may be marked throughout thespecification and drawing with the same reference numerals,respectively. The drawing figures are not necessarily to scale andcertain features may be shown exaggerated in scale or in somewhatgeneralized or schematic form in the interest of clarity andconciseness.

An actuating sphere is a large bead or other bearing-type objectcomprised of a low-density, mechanically elastic material, which isprepared using any suitable technique, for example injection molding,compression molding, or cast material over a core. The actuating spheremay be made from ionomeric resins, polyurethanes, silicon, and othermaterials. The actuating sphere, while having a generally sphericalouter surface, may have a plurality of dimples or other indentations orprotrusions for optimized aerodynamic properties as well as for improvedretention of active agents. The actuating sphere is utilized in thecontext of providing a medium for attachment of active agents, thusreleasing the active agent upon the introduction of force or inertia.

An actuator is a bead or other bearing-type object to which a medicamentis adhered, and that oscillates in response to air flow. An actuatingsphere is one kind of actuator.

Active Pharmaceutical Ingredients; Active Agents:

Active pharmaceuticals ingredients (APIs), or active agents, may includeanalgesic anti-inflammatory agents such as, acetaminophen, aspirin,salicylic acid, methyl salicylate, choline salicylate, glycolsalicylate, 1-menthol, camphor, mefenamic acid, fluphenamic acid,indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxene,pranoprofen, fenoprofen, sulindac, fenbufen, clidanac, flurbiprofen,indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic acid,bendazac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone,clofezone, pentazocine, mepirizole, and the like.

Drugs having an action on the central nervous system, for examplesedatives, hypnotics, antianxiety agents, analgesics and anesthetics,such as, chloral, buprenorphine, naloxone, haloperidol, fluphenazine,pentobarbital, phenobarbital, secobarbital, amobarbital, cydobarbital,codeine, lidocaine, tetracaine, dyclonine, dibucaine, cocaine, procaine,mepivacaine, bupivacaine, etidocaine, prilocalne, benzocaine, fentanyl,nicotine, and the like. Local anesthetics such as, benzocaine, procaine,dibucaine, lidocaine, and the like.

Antihistaminics or antiallergic agents such as, diphenhydramine,dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyclizine,promethazine, carbinoxamine, tripelennamine, brompheniramine,hydroxyzine, cyclizine, meclizine, clorprenaline, terfenadine,chlorpheniramine, and the like. Anti-allergenics such as, antazoline,methapyrilene, chlorpheniramine, pyrilamine, pheniramine, and the like.Decongestants such as, phenylephrine, ephedrine, naphazoline,tetrahydrozoline, and the like.

Antipyretics such as, aspirin, salicylamide, non-steroidalanti-inflammatory agents, and the like. Antimigrane agents such as,dihydroergotamine, pizotyline, and the like. Acetonide anti-inflammatoryagents, such as hydrocortisone, cortisone, dexamethasone, fluocinolone,triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone,halcinonide, methylprednisolone, fludrocortisone, corticosterone,paramethasone, betamethasone, ibuprophen, naproxen, fenoprofen,fenbufen, flurbiprofen, indoprofen, ketoprofen, suprofen, indomethacin,piroxicam, aspirin, salicylic acid, diflunisal, methyl salicylate,phenylbutazone, sulindac, mefenamic acid, meclofenamate sodium,tolmetin, and the like. Muscle relaxants such as, tolperisone, baclofen,dantrolene sodium, cyclobenzaprine.

Steroids such as, androgenic steriods, such as, testosterone,methyltestosterone, fluoxymesterone, estrogens such as, conjugatedestrogens, esterified estrogens, estropipate, 17β estradiol, 17βestradiol valerate, equilin, mestranol, estrone, estriol, 17β ethinylestradiol, diethylstilbestrol, progestational agents, such as,progesterone, 19-norprogesterone, norethindrone, norethindrone acetate,melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate,hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17-αhydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol,norgestrel, demegestone, promegestone, megestrol acetate, and the like.

Respiratory agents such as, theophilline and β-adrenergic agonists, suchas, albuterol, terbutaline, metaproterenol, ritodrine, carbuterol,fenoterol, quinterenol, rimiterol, solmefamol, soterenol, tetroquinol,tacrolimus and the like. Sympathomimetics such as, dopamine,norepinephrine, phenylpropanolamine, phenylephrine, pseudoephedrine,amphetamine, propylhexedrine, arecoline, and the like.

Antimicrobial agents including antibacterial agents, antifungal agents,antimycotic agents and antiviral agents; tetracyclines such as,oxytetracycline, penicillins, such as, ampicillin, cephalosporins suchas, cefalotin, aminoglycosides, such as, kanamycin, macrolides such as,erythromycin, chloramphenicol, iodides, nitrofrantoin, nystatin,amphotericin, fradiomycin, sulfonamides, purroInitrin, clotrimazole,itraconazole, miconazole chloramphenicol, sulfacetamide, sulfamethazine,sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole;antivirals, including idoxuridine; clarithromycin; and otheranti-infectives including nitrofurazone, and the like.

Antihypertensive agents such as, clonidine, a-methyldopa, reserpine,syrosingopine, rescinnamine, cinnarizine, hydrazine, prazosin, and thelike. Antihypertensive diuretics such as, chlorothiazide,hydrochlorothrazide, bendoflumethazide, trichlormethiazide, furosemide,tripamide, methylclothiazide, penfluzide, hydrothiazide, spironolactone,metolazone, and the like. Cardiotonics such as, digitalis,ubidecarenone, dopamine, and the like. Coronary vasodilators such as,organic nitrates such as, nitroglycerine, isosorbitol dinitrate,erythritol tetranitrate, and pentaerythritol tetranitrate, dipyridamole,dilazep, trapidil, trimetazidine, and the like. Vasoconstrictors suchas, dihydroergotamine, dihydroergotoxine, and the like. β-blockers orantiarrhythmic agents such as, timolol pindolol, propranolol, and thelike. Humoral agents such as, the prostaglandins, natural and synthetic,for example PGE1, PGE2α, and PGF2α, and the PGE1 analog misoprostol.Antispasmodics such as, atropine, methantheline, papaverine,cinnamedrine, methscopolamine, and the like.

Calcium antagonists and other circulatory organ agents, such as,aptopril, diltiazem, nifedipine, nicardipine, verapamil, bencyclane,ifenprodil tartarate, molsidomine, clonidine, prazosin, and the like.Anti-convulsants such as, nitrazepam, meprobamate, phenytoin, and thelike. Agents for dizziness such as, isoprenaline, betahistine,scopolamine, and the like. Tranquilizers such as, reserprine,chlorpromazine, and antianxiety benzodiazepines such as, alprazolam,chlordiazepoxide, clorazeptate, halazepam, oxazepam, prazepam,clonazepam, flurazepam, triazolam, lorazepam, diazepam, and the like.

Antipsychotics such as, phenothiazines including thiopropazate,chlorpromazine, triflupromazine, mesoridazine, piperracetazine,thioridazine, acetophenazine, fluphenazine, perphenazine,trifluoperazine, and other major tranqulizers such as, chlorprathixene,thiothixene, haloperidol, bromperidol, loxapine, and molindone, as wellas, those agents used at lower doses in the treatment of nausea,vomiting, and the like.

Drugs for Parkinson's disease, spasticity, and acute muscle spasms suchas levodopa, carbidopa, amantadine, apomorphine, bromocriptine,selegiline (deprenyl), trihexyphenidyl hydrochloride, benztropinemesylate, procyclidine hydrochloride, baclofen, diazepam, dantrolene,and the like. Respiratory agents such as, codeine, ephedrine,isoproterenol, dextromethorphan, orciprenaline, ipratropium bromide,cromglycic acid, and the like. Non-steroidal hormones or antihormonessuch as, corticotropin, oxytocin, vasopressin, salivary hormone, thyroidhormone, adrenal hormone, kallikrein, insulin, oxendolone, and the like.

Vitamins such as, vitamins A, B, C, D, E and K and derivatives thereof,calciferols, mecobalamin, and the like for use dermatologically. Enzymessuch as, lysozyme, urokinaze, and the like. Herb medicines or crudeextracts such as, Aloe vera, and the like.

Antitumor agents such as, 5-fluorouracil and derivatives thereof,krestin, picibanil, ancitabine, cytarabine, and the like. Anti-estrogenor anti-hormone agents such as, tamoxifen or human chorionicgonadotropin, and the like. Miotics such as pilocarpine, and the like.

Cholinergic agonists such as, choline, acetylcholine, methacholine,carbachol, bethanechol, pilocarpine, muscarine, arecoline, and the like.Antimuscarinic or muscarinic cholinergic blocking agents such as,atropine, scopolamine, homatropine, methscopolamine, homatropinemethylbromide, methantheline, cyclopentolate, tropicamide,propantheline, anisotropine, dicyclomine, eucatropine, and the like.

Mydriatics such as, atropine, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine, hydroxyamphetamine, and the like. Psychicenergizers such as 3-(2-aminopropy)indole, 3-(2-aminobutyl)indole, andthe like.

Antidepressant drugs such as, isocarboxazid, phenelzine,tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin,desipramine, nortriptyline, protriptyline, amoxapine, maprotiline,trazodone, and the like.

Anti-diabetics such as, insulin, and anticancer drugs such as,tamoxifen, methotrexate, and the like.

Anorectic drugs such as, dextroamphetamine, methamphetamine,phenylpropanolamine, fenfluramine, diethylpropion, mazindol,phentermine, and the like.

Anti-malarials such as, the 4-aminoquinolines, alphaaminoquinolines,chloroquine, pyrimethamine, and the like.

Anti-ulcerative agents such as, misoprostol, omeprazole, enprostil, andthe like.

Antiulcer agents such as, allantoin, aldioxa, alcloxa,N-methylscopolamine methylsuflate, and the like. Antidiabetics such asinsulin, and the like.

Anti-cancer agent such as, cis-platin, actinomycin D, doxorubicin,vincristine, vinblastine, etoposide, amsacrine, mitoxantrone,tenipaside, taxol, colchicine, cyclosporin A, phenothiazines orthioxantheres, and the like.

For use with vaccines, one or more antigens, such as, natural,heat-killer, inactivated, synthetic, peptides and even T cell epitopes(e.g., GADE, DAGE, MAGE, etc.) and the like.

Example therapeutic or active agents also include drugs of molecularweight from 40 to 1,100 including the following: Hydrocodone, Lexapro,Vicodin, Effexor, Paxil, Wellbutrin, Bextra, Neurontin, Lipitor,Percocet, Oxycodone, Valium, Naproxen, Tramadol, Ambien, Oxycontin,Celebrex, Prednisone, Celexa, Ultracet, Protonix, Soma, Atenolol,Lisinopril, Lortab, Darvocet, Cipro, Levaquin, Ativan, Nexium,Cyclobenzaprine, Ultram, Alprazolam, Trazodone, Norvasc, Biaxin,Codeine, Clonazepam, Toprol, Zithromax, Diovan, Skelaxin, Klonopin,Lorazepam, Depakote, Diazepam, Albuterol, Topamax, Seroquel,Amoxicillin, Ritalin, Methadone, Augmentin, Zetia, Cephalexin, Prevacid,Flexeril, Synthroid, Promethazine, Phentermine, Metformin, Doxycycline,Aspirin, Remeron, Metoprolol, Amitriptyline, Advair, Ibuprofen,Hydrochlorothiazide, Crestor, Acetaminophen, Concerta, Clonidine, Norco,Elavil, Abilify, Risperdal, Mobic, Ranitidine, Lasix, Fluoxetine,Coumadin, Diclofenac, Hydroxyzine, Phenergan, Lamictal, Verapamil,Guaifenesin, Aciphex, Furosemide, Entex, Metronidazole, Carisoprodol,Propoxyphene, Digoxin, Zanaflex, Clindamycin, Trileptal, Buspar, Keflex,Bactrim, Dilantin, Flomax, Benicar, Baclofen, Endocet, Avelox, Lotrel,Inderal, Provigil, Zantac, Fentanyl, Premarin, Penicillin, Claritin,Reglan, Enalapril, Tricor, Methotrexate, Pravachol, Amiodarone, Zelnorm,Erythromycin, Tegretol, Omeprazole, and Meclizine.

Other active agents include those listed as BCS Class II agents.

The active agents mentioned above may be used in combination asrequired. Moreover, the above drugs may be used either in the free formor, if capable of forming salts, in the form of a salt with a suitableacid or base. If the drugs have a carboxyl group, their esters may beemployed.

FIGS. 2A-2C illustrate certain principles utilized by embodiments of theinvention. In

FIG. 2A, an actuator 201 resides in a chamber 202. As will be explainedin more detail below, a powdered medicament is adhered to actuator 201.The powdered medicament may be in a pure form, or may be adhered tocarrier particles. The medicament may attach to actuator 201 by van derWaals forces, which may include combinations of permanent dipoles,induced dipoles, and instantaneous dipoles. Other attachment mechanismsmay also be used, alternatively or additionally. For example, theadhesion forces may arise from van der Waals forces, electrostaticinteractions, physical interactions, capillary interactions, orcombinations thereof. The air 203 is drawn into chamber 202 throughinlet channel 204. Inlet channel 204 is smaller in cross sectional areathan the size of actuator 201, so that actuator 201 cannot enter inletchannel 204. A retaining member 205 at the other end of chamber 202prevents actuator 201 from exiting that end of chamber 202. Retainingmember 205 may be, for example, a mesh or grid that permits flow of airthrough the retaining member, but retains actuator 201 within chamber202. In some embodiments, retaining member 205 may define openings thatare about 250 microns in breadth, so as to prevent the passage ofparticles larger than about 250 microns. In other embodiments, retainingmember 205 may define openings that are about 500 microns in breadth, soas to prevent the passage of particles larger than about 500 microns.Other sieve sizes are also possible. In some embodiments, retainingmember 205 may have less than 50% occluded area, and in otherembodiments more than 50% occluded area. When the sizes of actuator 201,chamber 202, and inlet channel 204 are properly chosen, flow of airthrough the system causes actuator 201 to oscillate rapidly generally inthe axial direction of the flow.

An actuator useful in embodiments of the invention and exemplified byactuator 201 may be spherical or approximately spherical, but may haveother shapes as well, for example elliptical, polyhedral, or othershapes. An actuator may be smooth, or have indentations, dimples,protrusions, or other surface features. An actuator may be made of anysuitable material, for example a polymer such as polystyrene,polytetrafluorethylene, or another kind of polymer, polyurethane,silicon, silicone glass, silica gel, another glass, another gel, oranother kind of material or combination of materials. An actuator may bemade of a biodegradable material or a nonbiodegradable material. Manyother kinds of materials or combinations of materials may be used. Anactuator may have a relatively low density, for example, between 0.001and 0.5 g/cm³, or preferably between 0.001 and 0.12 g/cm³, or morepreferably between 0.001 and 0.04 g/cm³. An actuator may be of anyappropriate size compatible with the chamber in which it is retained.For example, an actuator may have a diameter or other largest dimensionof between 500 and 25000 microns (0.5 and 25 mm), preferably between1000 and 10000 microns (1.0 and 10.0 mm), and more preferably between1000 and 6000 microns (1.0 and 6.0 mm). An actuator may be made by anysuitable process, depending on the material of the actuator. Forexample, actuators may be made by molding, extrusion, milling, spraydrying, polymer imprinting, or other processes or combinations ofprocesses. In some embodiments, an actuator may have a mass of less than10.0 mg, for example less than 5.0 mg, or less than 2.5 mg. In otherembodiments, an actuator may have a mass of greater than 0.001 mg, forexample greater than 0.1 mg, or greater than 0.5 mg. In someembodiments, an actuator may have a mass between 0.001 mg and 10.0 mg,for example, between 0.1 mg and 5.0 mg, or between 0.5 mg and 2.5 mg.

FIG. 2B illustrates the formation of re-circulating eddies 206 in emptychamber 202. As the flow stream enters chamber 202, the flow streamdetaches from the inner wall of the system at the corner of theexpansion, where inlet channel 204 opens to chamber 202, and reattachesdownstream. At the corner of this expansion, part of the incoming flowstream is shed, becoming trapped as recirculating eddies 206 at thecorners 207 of chamber 202. Once actuator 201 is introduced into chamber202, the flow may become more complex. The net result is that actuator201 oscillates rapidly, generally along the axis of chamber 202.Actuator 201 may also rotate in up to three dimensions.

FIG. 2C is a multiple-exposure photograph of an actual system, in whichactuator 201 oscillates. It has been surprisingly discovered that duringoscillation, actuator 201 rarely contacts the walls or ends of chamber202. However, the oscillations of actuator 201 are sufficient inmagnitude to dislodge powdered medicament from the surface of actuator201.

This is in part due to the relatively large size of actuator 201, ascompared with carrier particles used in previous inhalers. The adhesiveforces holding powdered medicament to a carrier particle may beapproximated by

$F_{adhesive} = \frac{A_{H}d_{1}d_{2}}{12{D^{2}\left( {d_{1} + d_{2}} \right)}}$

where A_(H) is the Hamaker's constant, and is typically on the range of10⁻¹⁹ J, D is the interparticulate distance and is commonly given as 4Angstroms (10⁻¹⁰ m), and d₁ and d₂ are the diameters of the medicamentand carrier particles respectively. The separation forces generated bythe oscillation of actuator 201 are generally proportional to the cubeof the diameter of actuator 201. Thus, for a large actuator, it ispossible to generate separation forces that exceed the adhesive forces,as shown in FIG. 3, in region 301.

According to embodiments of the invention, these principles are utilizedto produce an inhaler with improved performance.

Inhaler Embodiments

FIG. 4A shows an oblique view of a dry powder inhaler (DPI) 400,according to an embodiment of the invention. DPI 400 includes amouthpiece 401, through which outlet channel 402 passes. DPI 400 alsoincludes a chamber portion 403, engaged with mouthpiece 401. DPI 400 mayalso include retaining features 404, for holding mouthpiece 401 andchamber portion 403 together. Connection features 404 may be releasable,to allow mouthpiece 401 and chamber portion 403 to be separated andreattached, for example for loading of DPI 400. Any suitable connectionmechanism may be used. FIG. 4B shows a side view of DPI 400, and FIG. 4Cshows a section view of DPI 400, revealing some internal details.

Chamber portion 403 of DPI 400 includes an inlet channel 405, leading toa chamber 406. Optionally, the inside surface of chamber 406 may includeridges or other surface features to minimize the contact area of anactuator contained in chamber 406 with the walls. Chamber 406 has alarger cross sectional area than does inlet channel 405, and at theentrance 407 of chamber 406, the flow path of air through DPI 400undergoes a step increase in cross sectional area. Chamber 406 is of asize and shape to contain an actuator to which a powdered medicament isadhered. DPI 400 also includes a retaining member 407 downstream ofchamber 406. Retaining member 407 includes openings (not visible in FIG.4C) sized to permit air to flow through retaining member 408, but toretain the actuator within chamber 406. Retaining member may be, forexample, a mesh or grid placed across an end of chamber 406 or outletchannel 402.

FIG. 4D illustrates DPI 400 in operation. In FIG. 4D, an actuator 409has been loaded into chamber 406. Actuator 409 is large enough that itcannot pass through inlet channel 405 and cannot pass through theopenings in retaining member 408, and thus actuator 409 is retainedwithin chamber 406. Actuator 409 may be spherical or substantiallyspherical, although this is not a requirement. Because actuator 409 doesnot leave chamber 406 or come into contact with the patient, it need notbe made of lactose, and more flexibility in the selection of materialsfor actuator 409 is provided than for the carrier particles in aconventional inhaler. Actuator 409 may be, for example, made ofpolystyrene, polytetrafluoroethylene (PTFE, aka Teflon), silicone glass,silica gel, glass, or another suitable material. In some embodiments,actuator 409 may be made of a biodegradable material.

Particles 410 of a powdered medicament (shown exaggerated in size inFIG. 4D) are adhered to actuator 409. A patient places mouthpiece 401 inhis or her mouth, and inhales. The inspiratory effort of the patientdraws air 411 into inlet channel 405. As previously explained, actuator409 oscillates generally along the axial direction of the flow channel,dislodging particles 410 from the surface of actuator 409 such that theyare entrained in the flow stream.

The dislodged particles 410 pass through retaining member 408, throughoutlet channel 402, and exit DPI 400 to be inhaled by the patient.Outlet channel 402 may include ridges or grooves (similar to the riflingin the barrel of a firearm) to assist in directing the flow of themedicament in a straight path as it leaves the device. Actuator 409 mayoscillate many of times during a single inhalation, and may oscillate asmany as hundreds of times. The oscillation frequency is typicallybetween 1 and 1000 Hz, and is preferably between 25 and 150 Hz, althoughother frequencies may also occur. The oscillation may produce an audiblesound, which can provide audible feedback to a patient using the DPI,indicating that medicament is being delivered.

These oscillations impart much more force to the actuator than isimparted to a lactose carrier particle during collisions in aconventional inhaler.

An inhaler that is actuated by the patient's inspiratory effort alone isknown as a passive inhaler. It will be recognized that the invention maybe embodied in a passive inhaler, or an inhaler that uses another energysource at least in part to promote air flow.

Within this basic framework, many variations are possible. FIG. 5A showsan oblique view of a DPI 500 according to another embodiment. DPI 500includes several features similar to features of DPI 400 previouslydescribed, including a mouthpiece 501 including an outlet flow channel502. DPI 500 also includes flow bypass channels 503 that are connectedto a sheath flow channel 504. FIG. 5B is a cross section view of DPI500, showing the internal configuration of flow bypass channels 503 andsheath flow channel 504. Supplemental air 505 is drawn into flow bypasschannels 505 and through sheath flow channel 504, reaching the patientwithout having passed through chamber 506. Flow bypass channels may beincluded to reduce the flow resistance of DPI 500, while still allowingsufficient airflow through chamber 506 to deliver powdered medicament tothe patient. For example, in a direct comparison, a device withoutbypass flow channels was measured to have a flow resistance of about0.140 (cmH₂O)^(0.5)/L min⁻¹, resulting in a flow rate of about 46 Lmin⁻¹ with a pressure drop of 4 kPa across the inhaler, while a devicewith bypass flow channels was measured to have a flow resistance ofabout 0.061 (cmH₂O)^(0.5)/L min⁻¹, resulting in a flow rate of about 105L min⁻¹ with a pressure drop of 4 kPa across the inhaler.

In another variation, FIG. 6 illustrates a cross section of analternative chamber portion 601. Chamber portion 601 is similar tochamber portion 403 described above, but rather than a cylindrical inletflow channel, chamber portion 601 includes a tapered inlet flow channel602. Many other shapes are possible.

FIG. 7 illustrates a cross section view of a DPI 700 according toanother embodiment, including dimensions of various features, given inmillimeters. DPI 700 may accommodate an actuator having a diameter ofabout 4.5-5.5 millimeters, although other sizes may be used. DPI 700includes a mouthpiece 701 having an outlet flow channel 702. Unlikeoutlet flow channel 402 described above, outlet flow channel 702 is notcylindrical, but changes in cross sectional area along its length. Achamber portion 703 includes an inlet flow channel 704 (which is taperedin this example), leading to a chamber 705. Bypass flow channels 706direct supplemental air to a sheath flow channel 707 without thesupplemental air having passed through chamber 705.

While DPI 700 serves as one enabling example embodiment, it will beunderstood that the invention claimed is not limited to the particulardimensions or combination of features shown. For example, the length ofmouthpiece 701 may be shorter or longer than that shown in FIG. 7.Outlet flow channel 702 may be cylindrical or may have a cross sectionalarea that varies along the length of mouthpiece 701. The two ends ofoutlet flow channel 702 may be of equal size, or may differ in size,with either end being larger than the other. Cylindrical flow channelsneed not be circularly cylindrical, but may have cross sectional shapesin the form of polygons, ellipses, or other shapes. The length of inletflow channel 704 may be varied, and inlet flow channel 704 may becylindrical or may have a cross sectional area that varies along thelength of inlet flow channel 704. Inlet flow channel 704 may bestraight, tapered, curved, angled, or have another shape. Bypass flowchannels 706 and sheath flow channel 707 may be varied in shape or size,or may be omitted. For example, sheath flow channel 707 may be straight,curved, tapered, angled, or may have another shape. A different numberof bypass flow channels 706 may be provided. Multiple sheath flowchannels 707 may be provided. The length, shape, and cross sectionalarea of chamber 705 may be varied from the stated dimensions, within anyworkable ranges.

In some embodiments, the ratio of the chamber diameter to the inletdiameter is between 1.5 and 3.0, for example between 2.10 and 2.25. Insome embodiments, the ratio of the chamber diameter to the diameter ofthe actuator within the chamber is between 1.0 and 2.0, for examplebetween 1.3 and 1.6.

Mouthpiece 701 and chamber portion 703 may be made of any suitablematerial, but preferably are molded of a medical or food grade polymersuch as polycarbonate, ABS, or another polymer or blend of polymers. Theparts of DPI 700 may be reusable or may be disposable.

The embodiment of FIG. 7 was measured to have a flow resistance of about0.059 (cmH₂O)^(0.5)/L min⁻¹. Its performance was tested in vitro using acascade impactor, at a volumetric flow rate of 90 L min⁻¹, whichcorresponds to approximately a 2 kPa pressure drop across the inhaler.Several medicaments were tested, and results are shown below in Table 1.

For the fluticasone propionate and salmeterol xinafoate drug-coatedbeads, coating was performed according to the piezo-assisted coating(PAC) technique. Briefly, 2 mg of micronized drug powder were weighedinto a 30-mL scintillation vial containing three 5.2 mm polystyrenebeads. The vial was sealed and the bottom half was submerged in asonicating water bath for 2 minutes. When the vial was placed in thewater bath, the energy imparted to the powder by the sonics aerosolizeda fraction of the powder bed, creating a sustained plume as powder wascontinuously aerosolized and then deposited onto the bead surface bygravitational settling. Due to the small size, and thus negligible mass,of the primary drug particles, van der Waals interactions may overwhelmother types of forces, including gravitational forces. Other kinds offorces may also contribute to attachment of powder to the actuator, forexample forces arising from electrostatic interactions, physicalinteractions, capillary interactions, or others. More information aboutthe deposition of medicament on beads may be found in co-pending PCTPatent Application PCT/US2010/047043, published as WO/2011/031564, theentire disclsoure of which is hereby incorporated by reference herein.

For fluticasone propionate and salmeterol xinafoate, drug depositing oneach component of the experimental setup (bead, device, mouthpieceadaptor, USP induction port, and cascade impactor stages) was assessedvia high performance liquid chromatography (HPLC). The fine particlefraction of the delivered dose was calculated as the ratio of the drugmass collected from stages 2-8 of the cascade impactor over the drugmass emitted from the device.

TABLE 1 Fine particle fractions (FPF) values of the dose delivered fromthe single-chamber dry powder inhaler at a volumetric flow rate of 90 Lmin⁻¹ (approx. 2 kPa pressure drop across the device). Values arepresented as the mean (±standard deviation) for N = 3 replicates. APIFine Particle Fraction (%) Salbutamol Sulphate 84.2 (0.9) SalmeterolXinafoate 88.5 (3.0) Fluticasone Propionate 80.5 (1.5) TiotropiumBromide 85.2 (1.5)

In the embodiments described thus far, a single chamber is provided, forholding a single actuator. The single actuator may have a singlepowdered medicament adhered to it, or may have a mixture of powderedmedicaments adhered to it, so that a combination of drugs may bedelivered.

In another variation, multiple chambers may be provided, for holdingmultiple actuators. For example, multiple actuators may have the samemedicament or medicaments adhered to them, for delivering a strongerdose than is delivered from a single actuator, or may have differentmedicaments adhered to them for delivering a combination of drugs.

FIG. 8A illustrates an oblique view of a chamber portion 801 inaccordance with another embodiment. Chamber portion 801 includes twochambers 802 a and 802 b, and two inlet flow channels 803 a and 803 b.FIG. 8B shows a cross section view of chamber portion 801, and includesexample dimensions. The embodiment of FIGS. 8A and 8B may accommodateactuators having diameters between about 3.8 and 4.4 millimeters.

FIGS. 8C and 8D illustrate two alternative arrangements for connectingthe multiple chambers 802 a and 802 b to one or more outlet flowchannels. In the embodiment of FIG. 8C, both chambers 802 a and 802 bare connected to a single outlet flow channel 804. In the embodiment ofFIG. 8D, chambers 802 a and 802 b are connected to different respectiveoutlet flow channels 805 a and 805 b.

To assess the aerosol performance of the dual chamber devices (using thesame inhaler base, with the type of mouthpiece being varied) in vitro,beads coated with fluticasone and salmeterol (using the PAC method) wereactuated at 90 L min⁻¹ (corresponding to approximately a 2 kPa pressuredrop across the device) into a next generation cascade impactor. Drugdepositing on each component of the experimental setup (bead, device,mouthpiece adaptor, USP induction port, and cascade impactor stages) wasassessed via high performance liquid chromatography (mobile phase=75:25mixture of methanol and 0.8% (w/v) ammonium acetate buffer at a pH of5.5; stationary phase=5 μm C₁₈; detection wavelength=228 nm). The fineparticle fraction of the delivered dose was calculated as the ratio ofthe drug mass collected from stages 2-8 of the cascade impactor over thedrug mass emitted from the device, corresponding to an aerodynamicdiameter cut-off size of 6.48 μm (at 90 L min⁻¹).

The performance of the embodiment of FIG. 8C is summarized in Table 2.

TABLE 2 Fine particle fractions (FPF) values of the dose delivered froma dual- chamber dry powder inhaler at a volumetric flow rate of 90 Lmin⁻¹ (approx. 2 kPa pressure drop across the device). Values arepresented as the mean (±standard deviation) for N = 3 replicates. FineParticle API Fraction (emitted) (%) Fluticasone Propionate 76.8 (1.8)Salmeterol Xinafoate 49.1 (5.1)

The performance of the embodiment of FIG. 8D is summarized in Table 3.

TABLE 3 Fine particle fractions (FPF) values of the dose delivered froma dual- chamber dry powder inhaler with separate powder flow channels ata volumetric flow rate of 90 L min⁻¹ (approx. 2 kPa pressure drop acrossthe device). Values are presented as the mean (±standard deviation) forN = 3 replicates. Fine Particle API Fraction (emitted) (%) FluticasonePropionate 77.5 (1.6) Salmeterol Xinafoate 54.1 (9.4)

FIG. 9A illustrates an oblique view of a chamber portion 901 inaccordance with another embodiment. Chamber portion 901 includes threechambers 902 a, 902 b, and 902 c, and three inlet flow channels. FIG. 9Bshows a cross section view of chamber portion 901, and includes exampledimensions. Only inlet flow channel 903 a is visible in FIG. 9B. Theembodiment of FIGS. 9A and 9B may accommodate actuators having diametersbetween about 3.2 and 3.8 millimeters.

FIG. 9C illustrates the use of chamber portion 901 with a mouthpiecehaving a single outlet flow channel 904 to which all three of chambers902 a, 902 b, and 902 c deliver air and medicament. It will beunderstood that a mouthpiece could also be used having a separaterespective outlet flow channel for each of chambers 902 a, 902 b, and902 c.

The examples above show dual and triple chambers, wherein the overalldiameter of the inhaler has been kept constant, requiring that thedimensions of the chambers and inlet flow channels be reduced and thatsmaller actuators be used as compared with the single-chamberembodiments. This is not a requirement. The overall dimensions of theinhaler may be also be varied if desired.

While the embodiments of FIGS. 8A-9C serve as enabling exampleembodiments, it will be understood that the dimensions and combinationsof features shown are by way of example, and that may variations arepossible.

The embodiments described above are also configured for oral inhalationof powdered medicament. Devices embodying the invention may also beconfigured to deliver medicament nasally, either in place of or inaddition to oral delivery. For example, the outlet flow channel orchannels may be comprised in a nasal adapter.

Cartridge

According to another aspect, a cartridge is provided with a pre-loadedactuator. Such a cartridge may contain a single dose of a powderedmedicament, and may be loaded into a reusable DPI that operatesaccording to the principles of the invention.

FIG. 10 illustrates a cartridge 1000, in accordance with an embodiment.Cartridge 1000 includes a first shell 1001 defining a first end of thecartridge. First shell 1001 includes a restriction 1002 that serves asan inlet flow channel. Cartridge 1000 also includes a second shell 1003that defines a second end of the cartridge. Second shell 1003 alsodefines at least a portion of a chamber 1004, and includes a retainingelement 1005. Retaining element 1005 may be a mesh or grid that spansthe cross section of second shell 1003. An actuator 1006 is alsoprovided, having one or more powdered medicaments adhered to it. Firstand second shells 1001 and 1003 are configured to engage to form thecompleted cartridge 1000, enclosing actuator 1006. The closed ends offirst and second shells 1001 and 1003 are formed by first and secondpuncturable seals 1007 and 1008, which also form the ends of cartridge1000 once first and second shells 1001 and 1003 are engaged. Each ofpuncturable seals 1007 and 1008 may be, for example an aluminum foil orplastic barrier that serves to keep contaminants out of cartridge 1000,but can be easily punctured (as described below) to open the ends ofcartridge 1000 for use. Retaining member 1005 has openings to permitmedicament dislodged from actuator 1006 to pass through retaining member1005 during use, but retaining member does not permit actuator 1006 toleave cartridge 1000. Thus, cartridge 1000 contains and protects theactuator and medicament until it is inserted into an inhaler for use. Insome embodiments, a cartridge may be used only once, to administer asingle dose of medicament.

Cartridges 1000 may be produced in large numbers and distributed toinhaler users for treatment of various conditions. FIG. 11 illustratesone example method of producing cartridges 1000. A number of firstshells 1001 are produced, and a number of actuators 1006 are producedand coated with medicament. Actuators 1006 are suspended on a string1101 for convenient handling by automated production equipment.Actuators 1006 are placed into first shells 1001, and second shells 1003are engaged with first shells 1001 to form completed cartridges 1000. Insome embodiments, the action of engaging the first and second shells1001 and 1003 cuts string 1101, so that the individual cartridges 1000are easily separable. Preferably, a portion of string 1101 remainswithin each cartridge 1000, suspending actuator 1006 so that it does notreadily contact the walls of the cartridge.

The act of loading one of cartridges 1000 into an inhaler may punctureseals 1007 and 1008, readying the cartridge for use. This process isillustrated in FIG. 12. A first portion 1201 of an inhaler is configuredto receive a first end of cartridge 1000. First portion 1201 includes alip 1202, on which cartridge 1000 rests when first loaded into firstportion 1201. A second portion 1203 of the inhaler, including a secondlip 1204, is then placed over cartridge 1000. When first and secondportions 1201 and 1203 are pressed together, lips 1202 and 1204 puncturethe seals at the ends of cartridge 1000, providing openings 1205 and1206 for the passage of air. In some embodiments, the action of pressingfirst and second inhaler portions 1201 and 1203 together furthercompresses cartridge 1000, causing string 1101 to be cut and freeingactuator 1006 so that it can oscillate during inhalation.

Multi-Dose Dry Powder Inhaler

According to another aspect, a multi-dose inhaler is provided. FIG. 13illustrates a multi-dose inhaler 1300 according to an embodiment.Multi-dose inhaler 1300 includes a mouthpiece portion 1301 and a roundbase portion 1302. A rotatable carriage 1303 is disposed within baseportion 1302, and includes a set of slots 1304 configured to receivecartridges, for example cartridges similar to cartridge 1000 describedabove. Each cartridge includes an actuator 1006, on which a powderedmedicament is adhered.

FIG. 14 illustrates multi-dose inhaler 1300 after loading. Oncemulti-dose inhaler 1300 is loaded, the user can rotate carriage 1303 toposition a fresh cartridge 1000 in line with outlet 1401, and inhale airthrough inhaler 1300. To receive another dose of medicament, the userrepeats the process with another fresh cartridge 1000.

Performance Examples

Tests have shown that devices according to embodiments may stilleffectively deliver medicament, even at low air flow rates, as comparedwith previous devices. Table 4 below compares the respirable fraction ofparticles produced by a DPI embodying the invention with that producedby a conventional inhaler using lactose carrier particles. Two differentmedicaments commonly prescribed for pulmonary disease were tested, thecorticosteroid budesonide and the β-agonist salbutamol, at threedifferent flow rates.

TABLE 4 Comparison of respirable fraction produced by embodiments of thepresent invention with prior lactose-based delivery Fine Particle FlowFraction (loaded) Rate Lactose Present Drug (L m⁻¹) Standard InventionBudesonide 45 28% 58% 30 26% 53% 15 5% 24% Salbutamol 45 47% 67% 30 46%68% 15 8% 45%

The relative insensitivity to flow rate may be especially important inthe treatment of patients having compromised breathing ability, forexample as a result of chronic obstructive pulmonary disease (COPD),which may make it difficult to use prior inhalers.

Testing has also shown that a DPI embodying the invention can includecoatings of a wide variety of medications in doses comparable to thosedelivered by prior commercial inhalers. These doses may range from lowdoses (for example the 12 mcg of formoterol delivered by the ForadilAerolizer and 22 mcg of tiotropium bromide delivered by the SpirivaHandihaler) to higher doses (for example 200 mcg of budesonide deliveredfrom the Pulmicort Turbuhaler DPI, or 500 mcg fluticasone delivered bythe Advair Diskus DPI).

In another comparison test, the performance of a dual-chamber DPIembodying the inventions was compared with the performance of a priorcommercial inhaler of a different design, in dispensing two differentmedicaments, fluticasone propionate and salmeterol xinafoate. Each ofthe two actuators in the DPI embodying the invention held one of the twomedicaments. The test results are shown in Tables 5A and 5B below. Table5A lists results for the prior commercial inhaler, and Table 5B listsresults for the DPI embodying the invention.

TABLE 5A Prior Commercial Inhaler Measured Performance PressureFluticasone Propionate Salmeterol Drop EF (%) FPF (%) RF (%) FPD (mcg)EF (%) FPF (%) RF (%) FPD (mcg) 4 kPa 100.2 (1.5)  21.8 (0.9) 21.8 (0.8)54.6 (2.0) 108.1 (5.1) 16.7 (0.9) 18.0 (0.5) 9.0 (0.3) 2 kPa 94.2 (8.8)23.8 (3.4) 22.3 (0.9) 55.6 (2.4) 108.2 (2.7) 15.9 (0.6) 17.2 (1.1) 8.6(0.5) 1 kPa 97.7 (5.0) 16.2 (0.6) 15.8 (0.8) 39.5 (2.0) 111.7 (6.3) 13.8(0.6) 15.4 (1.5) 8.4 (0.6)

TABLE 5B Dual Chamber DPI Embodying the Invention Measured PerformancePressure Fluticasone Propionate Salmeterol Drop EF (%) FPF (%) RF (%)FPD (mcg) EF (%) FPF (%) RF (%) FPD (mcg) 4 kPa 65.2 (1.6) 70.0 (2.7)45.7 (2.6) 69.1 (6.6) 56.6 (3.5) 78.2 (3.4) 45.5 (3.0) 16.6 (1.7) 2 kPa56.5 (0.3) 70.8 (2.5) 40.0 (1.4) 66.2 (6.1) 56.6 (4.3) 72.1 (3.2) 40.8(4.2) 15.0 (3.4) 1 kPa 48.1 (2.9) 61.7 (0.6) 29.7 (1.6) 46.7 (2.5) 42.9(4.6) 62.1 (5.6) 26.5 (0.3)  9.1 (1.5)In Tables 5A and 5B, emitted fraction (EF), fine particle fraction(FPF), respirable fraction (RF), and fine particle dose (FPD) valueswere determined in vitro for both inhalers. For the prior commercialinhaler, EF and RF are provided as the percentage of the labeled dose.All values are presented as mean (±standard deviation) for threereplicates. As is apparent, the DPI embodying the invention provides asignificantly higher medicament delivery, and also delivers significantdoses of medicament at low flow rates. The relatively low values of FPFachieved by the prior commercial inhaler are believed to be due to thefact that a significant portion of the powdered medicament remainedattached to the carrier particles used in that system, and did notemerge in respirable particle sizes. By contrast, in the DPI embodyingthe invention, only the powdered medicament, without carrier particles,emerges from the DPI, and thus a much larger percentage of the emittedmedicament is respirable.

In another comparison test, two adult human volunteer subjects werere-enrolled from a cohort of subjects who participated in a safety studyof inhaled Tacrolimus via nebulization (5 mg). Peak blood Tacrolimusconcentrations 1 hr post-inhalation in subjects exposed to drug bynebulization ranged from 5 to 8 ng/ml. In the current study, subjectsinhaled Tacrolimus via a DPI embodying the invention or HandiHaler DPIstandard on study days 1 or 8, respectively. Tacrolimus levels weremeasured from blood samples 1 hr post-inhalation. The results from thisstudy are summarized in Table 6 below.

TABLE 6 Comparison of blood level of Tacrolimus Fine Drug Particle Level1 hr Total Fraction Post- Ex- Powder (loaded) Inhalation DPI Drugcipients (μg) (%) (ng/ml) HandiHaler Tacrolimus Yes 2000 32 ± 3 7.7-10.0 DPI Tacrolimus No 1095 ± 123 68 ± 2 14.2-15.5 Embodying (pure)Invention

It is to be understood that any workable combination of any featuresdescribed herein is also considered to be disclosed. The invention hasnow been described in detail for the purposes of clarity andunderstanding. However, those skilled in the art will appreciate thatcertain changes and modifications may be practiced within the scope ofthe appended claims.

1. A dry powder inhaler, comprising: an inlet channel through which airenters the inhaler; a chamber that receives air from the inlet channel,the chamber being of a size and shape to contain an actuator to which apowdered medicament is adhered; a retaining member disposed at an end ofthe chamber opposite the inlet channel, the retaining member having oneor more openings sized to permit air and the powdered medicament to passthrough the retaining member, and to prevent the actuator from passingthrough the retaining member; and an outlet channel through which airand the powdered medicament leave the inhaler to be delivered to apatient; wherein the geometry of the inhaler is such that a flow profileis generated within the chamber that causes the actuator to oscillate,thus detaching the powdered medicament from the surface of the actuatorto be entrained by the air and delivered to the patient through theoutlet channel.
 2. The dry powder inhaler of claim 1, wherein the crosssectional area of the flow path through the inhaler undergoes a stepincrease at the entrance to the chamber.
 3. The dry powder inhaler ofclaim 2, wherein at the entrance to the chamber the diameter of thechamber is at least 1.5 times the diameter of the inlet channel.
 4. Thedry powder inhaler of claim 1, wherein the inlet channel comprises atapered tube.
 5. The dry powder inhaler of claim 1, wherein the outletchannel comprises a tube whose cross section changes along the length ofthe tube.
 6. The dry powder inhaler of claim 1, wherein the outletchannel is comprised in a mouthpiece adapted to be placed within themouth of the patient.
 7. The dry powder inhaler of claim 1, wherein theoutlet channel is comprised in a nasal adapter adapted to conform to thenostrils of the patient.
 8. The dry powder inhaler of claim 1, furthercomprising one or more bypass channels that receive supplemental airfrom outside the inhaler and deliver the supplemental air to the patientwithout the supplemental air having passed through the chamber.
 9. Thedry powder inhaler of claim 1, wherein the inlet channel is a firstinlet channel and the chamber is a first chamber, the dry powder inhalerfurther comprising a second inlet channel and a second chamber.
 10. Thedry powder inhaler of claim 9, wherein air and powdered medicamentleaving the first and second chambers are delivered to the outletchannel.
 11. The dry powder inhaler of claim 9, wherein the outletchannel is a first outlet channel, the dry powder inhaler furthercomprising a second outlet channel, and wherein air and powderedmedicament leaving the first chamber are delivered to the first outletchannel, and air and powdered medicament leaving the second chamber aredelivered to the second outlet channel.
 12. The dry powder inhaler ofclaim 9, wherein the first and second chambers are of the samedimensions.
 13. The dry powder inhaler of claim 1, wherein the drypowder inhaler is separable to permit insertion of a capsule into thechamber, the capsule containing the actuator.
 14. The dry powder inhalerof claim 13, further comprising features for puncturing seals at ends ofthe capsule.
 15. The dry powder inhaler of claim 1, wherein airflowthrough the inhaler is driven by inspiratory effort of the patient. 16.The dry powder inhaler of claim 1, in combination with the actuator. 17.The dry powder inhaler of claim 16, wherein the actuator is made ofexpanded polystyrene.
 18. The dry powder inhaler of claim 16, whereinthe actuator has a density between 0.001 and 0.50 g/cm³.
 19. The drypowder inhaler of claim 16, wherein the actuator has a diameter of atleast 1000 microns.
 20. The dry powder inhaler of claim 16, wherein theactuator has a diameter between 1000 and 6000 microns.
 21. The drypowder inhaler of claim 16, wherein the actuator has a mass of between0.1 and 5.0 milligrams.
 22. The dry powder inhaler of claim 16, whereinthe actuator has a mass of between 0.5 and 2.5 milligrams.
 23. The drypowder inhaler of claim 16, wherein a combination of medicaments isadhered to the actuator.
 24. The dry powder inhaler of claim 1,comprising a plurality of chambers disposed on a rotary element forselectively aligning any of the chambers with the outlet channel.
 25. Amethod, comprising: obtaining a dry power inhaler that includes an inletchannel, a chamber, and an outlet channel, the chamber holding anactuator, wherein one or more powdered medicaments are adhered to anoutside surface of the actuator; and inhaling through the outletchannel, causing air to flow into the inlet channel, through thechamber, and through the outlet chamber, the flowing air also causingthe actuator to oscillate to dislodge powdered medicament from thesurface of the actuator to be entrained in the flowing air and carriedthrough the outlet channel.
 26. The method of claim 25, furthercomprising: separating portions of the inhaler comprising the chamberand the outlet channel; loading the actuator into the chamber; andre-engaging the two portions of the inhaler.
 27. The method of claim 25,wherein a combination of powdered medicaments is adhered to theactuator.
 28. The method of claim 25, wherein the dry powder inhalerincludes at least two chambers holding at least two actuators havingmedicament adhered to the actuators, and wherein the flowing air causeseach actuator to oscillate to dislodge powdered medicament to beinhaled.
 29. The method of claim 28, wherein at least two actuators havethe same powdered medicament adhered to the actuators.
 30. The method ofclaim 28, wherein at least two actuators have different powderedmedicaments adhered to the actuators.